?1-adrenergic receptors (ARs) are G-protein coupled receptors (GPCRs) that respond to sympathetic hormones norepinephrine and epinephrine, and are therapeutic targets for the treatment of hypertension, benign prostrate hypertrophy (BPH), and post-traumatic stress disorder (PTSD). ?1-ARs comprise 3 unique subtypes, ?1A, ?1B, and ?1D, which are ubiquitously expressed on blood vessels throughout the CNS. Although each subtype responds to norepinephrine/epinephrine and activates G?q/11 signaling, the ?1D-AR subtype performs a specialized role using mechanisms distinct from the ?1A-AR and ?1B-AR subtypes. For example, ?1D-ARs stimulate vascular smooth muscle cell migration, while the ?1A and ?1B-AR subtypes stimulate vascular smooth cell hypertrophy. The molecular mechanisms that permit ?1D-ARs to selectively activate pathways distinct from those used by the ?1A and ?1B-AR subtypes remains a major mystery in the field. Revealing the molecular mechanisms ?1D- ARs use to stimulate vascular smooth cell migration will identify new drug targets to treat CNS blood vessel restenosis and atherosclerotic plaque formation, prevent migraine associated with malignant hypertension and reduce the potential for stroke and neuronal cell death. PUBLIC HEALTH RELEVANCE: This proposal will reveal how drugs affecting the adrenergic pathway (or fight or flight) in the body cause blood vessels to change in shape and function. This has important implications for adrenergic drugs currently used to treat high blood pressure, benign prostatic hypertrophy (BPH) in elderly males and post-traumatic stress disorder (PTSD) in combat veterans returning from Iraq and Afghanistan. This information will provide crucial information about the long-term safety of using these drugs in BPH, PTSD and cardiovascular disease.